The flavanone structure is abundant in natural products that possess a broad array of biological activity. Due to their favorable anti-tumor and anti-inflammatory properties, flavanones have been investigated as selective estrogen receptor modulators and TNF-α inhibitors. A limited number of strategies have been developed for the asymmetric synthesis of flavanones, such as resolution of the related alcohols or substitution reactions. Recently, an asymmetric copper(I)-catalyzed diethylzinc addition to 2-chromene was reported with high enantioselectivity. In this approach, the addition of benzaldehyde is required to trap the resulting zinc enolate. Ideally, asymmetric catalysis could provide a direct route to natural and synthetic flavanones that are currently difficult to access in optically active form. An enantioselective synthesis of flavanones that controls the C2 stereocenter remains a significant challenge due to the potential for reversible phenoxide elimination to form the achiral 2′-hydroxy chalcones. Accordingly, a route to enantioselective synthesis of flavanone and chromanone compounds remains an on-going concern in the art.
A related concern involves the abyssinones, a family of chiral, optically active flavanone natural products that display a diverse range of biological activities, including aromatase inhibition as well as antimicrobial, antimalarial activity. Despite their therapeutic promise, enantioenriched abyssinones have not been evaluated for their ability to inhibit cancer cell growth. This deficit is in large part due to the lack of efficient and stereoselective approaches for the synthesis of flavanones.
A limited number of strategies for the stereoselective synthesis of flavanones have been developed, including Mitsunobu reactions of chiral alcohols and acylation reactions of chiral ethers. Asymmetric conjugate addition reactions which are successful for dihydroquinolones (the nitrogen analogs of flavanones) are problematic due to undesired elimination reactions. As discussed above, the general structure of these molecules belies the challenge in executing a strategy that installs and maintains the configuration at the C2 position. This stereocenter is sensitive since basic conditions promote reversible ring opening to achiral 2′-hydroxy chalcones. Flavanones containing alkoxy- or hydroxy-substituents in the C4′ position are particularly susceptible to racemization due to stabilized benzylic cation formation.
Although extracts containing these compounds have been used as traditional remedies, any investigation of specific anti-cancer properties of the optically enriched abyssinones requires a general synthetic approach beyond natural product isolation. From this perspective, an enantioselective synthesis would lead to realization of the benefits and advantages afforded by such compounds.